Hospital Medicine

Dialysis

I. Problem/Challenge.

Kidney failure is worldwide public health problem, with increasing incidence and prevalence, high costs, and poor outcomes. When 90% or more of usual kidney function is lost, either kidney transplantation or dialysis is required to sustain life. In the United States, end stage renal disease (ESRD) is currently treated by hemodialysis (60%), peritoneal dialysis (10%), and renal transplantation (30%).

Although the overall incidence of ESRD is 348 cases per million population, blacks have a disproportionately high incidence rate of 979 cases per million, as compared with whites, with an incidence rate of 277 cases per million. Diabetes is the leading cause of ESRD in the United States, followed closely by hypertension, but among African Americans, ESRD attributed to hypertension is most common. Other causes of ESRD include primary and secondary glomerulopathies, cystic and interstitial renal diseases, and obstructive uropathy. Human immunodeficiency virus (HIV) is also an increasingly common cause of ESRD.

Chronic hemodialysis has been offered as an option for ESRD since the 1960s. The spread of dialysis centers across the US followed a 1972 law which required Medicare payment of 80% of the cost of dialysis for patients with ESRD. The average cost of providing care for a patient with hemodialysis (HD) is currently estimated to be around $66,000 a year. In 2007, inpatient expenditures for ESRD, including hemodialysis, peritoneal dialysis, and transplant totaled $39.46 billion, with $23.9 billion from Medicare, accounting for 5.8% of total Medicare expenditure.

Although chronic dialysis keeps many people alive who otherwise would have died from renal failure, it is far from an ideal form of treatment. Hemodialysis requires visits at least three times a week to a dialysis center for about 4 hours each visit, results in imperfect management of volume and electrolytes, and requires patients to adhere to a strict low sodium, potassium, phosphorus, and fluid restricted diet.

Mortality with hemodialysis remains high at approximately 18-20% per year, despite improvements in dialysis technology, the development of new pharmaceutical agents, and experience over the course of more than 40 years since maintenance dialysis became available. The most common cause of death of patients on chronic HD is coronary artery disease (CAD), followed by infection. Patients on HD, irrespective of the cause of their renal failure, are 10-20 times more likely to die from CAD than age-matched control subjects. More than half of patients started on chronic dialysis will die within the first 5 years. Moreover, although dialysis can sustain life, it rarely restores health; patients undergoing dialysis have considerable complications, including frequent and extended hospitalizations, and relatively poor functional status and health-related quality of life.

II. Identify the Goal Behavior

Dialysis mechanics

During dialysis, small molecules diffuse down their concentration gradient across a semipermeable membrane. In hemodialysis, blood is withdrawn from the patient’s body and passed through the hemodialyzer membrane that separates the blood from a dialysate solution on the other side, which contains electrolytes and glucose. In peritoneal dialysis, dialysate is infused into the abdominal cavity via a plastic catheter implanted in the peritoneal cavity and small molecules diffuse across the peritoneal membrane into the solution subsequently excreted in a drain bag.

Typical dialysate contains sodium, potassium, calcium, magnesium, chloride, glucose, and bicarbonate (or acetate or lactate) as buffer at concentrations similar to plasma, except for a high concentration of calcium and buffers, a low concentration of potassium, and a varied concentration of glucose. During dialysis, small molecules, such as urea, potassium, and phosphorus diffuse down their concentration gradients from the blood into the dialysate solution, while molecules such as calcium and bicarbonate (acetate or lactate) move down their concentration gradients from the dialysate solution into the blood. This results in a net effect of removal of metabolic waste products and the replenishment of body buffers and calcium.

The generation of an ultrafiltration pressure, either by manipulating the hydrostatic pressure across the hemodialyzer or the osmotic pressure across the peritoneal membrane, promotes the removal of excess fluid. The resulting improvement in urea clearance rates can cause a 65-70% reduction in blood urea nitrogen (BUN) concentration during a 3-4 hour treatment session.

Dialysis replaces the glomerular filtration rate (GFR) primarily by diffusion. Measurement of the delivered dose of dialysis has focused on the removal of urea, an easily measured surrogate marker for uremic toxins. The two most widely used measures of the adequacy of dialysis are calculated from the decrease in the BUN concentration during the treatment: the urea reduction ratio and Kt/V. The latter measure is an index based on urea clearance rate, K, and the size of the urea pool, represented by the urea distribution volume, V. T is the time spent in dialysis. The Kt/V index can be calculated by two methods: the blood and the dialysate kinetics.

The blood kinetic method is the most commonly used to estimate Kt/V during intermittent hemodialysis. The urea reduction ratio is measured by sampling only the blood at the start and end of hemodialysis. Currently a urea reduction ratio of 65% or a Kt/V of 1.2/treatment are minimal standards for adequacy of intermittent hemodialysis. The dialysate kinetic method is the most commonly used to estimate Kt/V during continuous peritoneal dialysis, whereby urea is measured in blood and in the total volume of dialysate excreted in the drain bag. Currently, a Kt/V of 1.7/week is the minimal standard for adequacy of peritoneal dialysis.

Side effects of dialysis

Hypotension is the most common adverse event during dialysis, usually caused by excessive ultrafiltration of fluid, leading to volume depletion. Apart from ultrafiltration, intermittent hemodialysis itself sometimes can cause hypotension by fluid movement inside the cell due to an osmotic disequilibrium across the cell membrane created by faster BUN removal from the extracellular than intracellular spaces.

Besides the extracellular volume depletion resulting from osmolar shifts, in some patients on intermittent hemodialysis, dialysate at 37C is associated with excess heat retention, which can cause vasodilatation and lower blood pressure. The use of a reduced temperature dialysis bath (35C) is helpful, as it can result in an increase in peripheral vascular resistance, elevation of plasma norepinephrine levels, improved myocardial contractility, and stable blood pressure.

Other potential life threatening causes of hypotension in dialysis patients can include myocardial ischemia, arrhythmia, or pericardial effusion/tamponade. Most hypotensive episodes are successfully treated by reducing the rate of ultrafiltration, administering intravenous saline, or both.

Another common side effect of dialysis is dialysis disequilibrium syndrome (DDS), characterized by neurologic symptoms that are thought to be due primarily to cerebral edema. New patients just starting on hemodialysis are at greatest risk, particularly if the BUN is markedly elevated (above 60mmol/L). Other predisposing factors include severe metabolic acidosis, older age, and the presence of other central nervous system (CNS) disease such as a preexisting seizure disorder. The rapid reduction in urea by hemodialysis is thought to be the cause of DDS. By lowering plasma osmolality, a transient osmotic gradient is created, which promotes water movement into cells, including the CNS.

Classically, DDS occurs during or immediately after dialysis. Findings include headache, nausea, asterixis, and disorientation, with more severely affected patients progressing to seizures, coma, and even death. Symptoms are usually self limited and dissipate within several hours. Prevention is the mainstay of therapy in DDS, particularly in new dialysis patients. The initial dialyses should achieve a gradual reduction in urea with a low blood flow rate along with a small surface area dialyzer.

Access

Obtaining and maintaining adequate access to the circulation remains a major impediment to the long-term success of hemodialysis. After initial placement, about $4000 and three hospital days per patient per year are spent maintaining access for dialysis. Hemodialysis access can come from several different ways, including a nontunnelled central venous catheter, a tunneled line, a Quinton catheter, arterial-venous (AV) fistula (using the patient’s own vasculature) or AV graft (using biosynthetic graft material). Both fistula and graft are surgical AV connections used to access a patient’s blood for dialysis. A fistula requires a period of maturation, and a graft a period of healing, before they can be used for hemodialysis.

Referral for AV fistula creation is recommended once the serum creatinine level increases to approximately 4mg/dl or the GFR is lower than 20ml/min. A large, thick walled fistula can be created by shunting blood from an artery to a vein. The result is the growth and thickening of the venous wall (a process called maturation), which should be completed in a few months and before the fistula is ready for repeated cannulations. Experts agree the best access for hemodialysis is the AV fistula, which is more durable and associated with less complications than the AV graft.

Referral for AV graft creation is recommended when the GRF is lower than 5ml/min and when hemodialysis is imminent within a few months. Grafts can be used sooner than fistulas, just a couple of weeks after creation and the healing of surgery. However, they are not as durable over time and are more prone to infection.

Use of cephalic and basilic veins for phlebotomy, intravenous cannulation, and peripherally inserted central catheter can prevent successful fistula or graft construction. Therefore, venipunction and intravenous (IV) cannulation above the level of the hands is contraindicated in chronic kidney disease. Peritoneal dialysis (PD) catheters should be placed approximately 1-3 months before PD therapy is initiated.

When dialysis is urgently required, a double lumen dialysis catheter is used. Insertion of the catheter into the subclavian vein is no longer common, as these catheters are associated with a high incidence of venous stenosis or thrombosis, and can interfere with future creation of an AV fistula or graft in the ipsilateral arm, or can cause chronic edema of the arm. Insertion in the jugular vein is the method of choice as it seems to result in less central venous injury. Temporary access can be used for 2-3 weeks, but clotting, low blood flow, and infection limits the life of the catheter.

Implantation of a dual lumen cuffed catheter (tunneled line) is a good option for patients who have delayed recovery from acute renal failure, who require access for dialysis until a fistula matures, or who lack another suitable site for graft placement. If carefully maintained, almost half of these catheters can be functional at one year.

The choice between peritoneal dialysis (PD) and hemodialysis (HD) for a specific patient depends on many factors. PD is limited by the amount of ultrafitrate that can be removed per exchange. One month after beginning PD, a peritoneal equilibration test is performed. Dialysate-to-plasma ratios of urea, creatinine, and glucose are compared, and transport is categorized as high, high average, low average, or low in PD patients. If a patient is found to be “low transport,” they may be precluded from undergoing PD, because this support therapy will not achieve adequate clearance.

If PD is an option for a patient, it is ideal for patients who wish to retain an active lifestyle, since dialysis sessions can be scheduled around work or school hours and overnight. Automated PD or use of a cycler can allow freedom from multiple daytime exchanges. Because of the more consistent control of extracellular volume and blood pressure, PD may be favored for patients with congestive heart failure (CHF) or unstable angina, who may not be able to tolerate the rapid fluid shifts or blood pressure swings that can accompany HD sessions. PD is also indicated for patients with extensive vascular disease that prevents the placement of an optimal vascular access.

HD is preferred for patients with mechanical gastrointestinal (GI) problems, such as abdominal hernias or adhesions that interfere with the PD procedure and for those with active GI conditions, including inflammatory bowel disease or diverticulitis. Patients for whom PD is inadequate, such as large patients, those with low PD clearance, and those with multiple episodes of peritonitis related to PD, should undergo HD. In addition, patients who are unable to be trained to perform PD exchanges or who cannot accept responsibility for self care are better suited for treatment with HD at a dialysis center.

In the United States, approximately 10% of ESRD patients undergo PD. Patient survival with this therapy is equivalent to in center hemodialysis in patients without diabetes. Data show that there is a slight increase in mortality in diabetic and elderly patients treated with chronic ambulatory peritoneal dialysis in the United States.

Dialysis delivery

At present, there is no uniform criterion for initiating renal replacement therapy (RRT) in non-emergent settings. In theory, early dialysis would improve nutritional status and cardiovascular complications, which would in turn lead to a decrease in mortality and the costs associated with these complications, though it would also expose patients to the complications of dialysis before it is strictly necessary, increasing the risk of infection and compromising quality of life. Most clinical practice guidelines recommend dialysis initiation when patients develop symptoms and/or signs of uremia unresponsive to medical therapy, usually occurring when the GFR falls below 6ml/min in chronic kidney disease (CKD).

In acute situations, dialysis should be initiated:

if life-threatening hyperkalemia with EKG changes are present

in severe volume overload with compromise of ventilation/oxygenation,

in cases of severe uremia/uremic pericarditis

in cases of severe acidosis

bleeding diathesis not resolved by other means.

In ESRD, options for dialysis delivery with hemodialysis include in-center dialysis and home hemodialysis. Almost 85% patients receive in-center hemodialysis, though better survival statistics are noted with home dialysis. Initial attempts to popularize daily dialysis in the United States were thwarted by unproven survival benefit, and financial and logistical issues Over the last decade, however, there has been a resurgence in the use of daily hemodialysis, with several studies emerging from the United States and Europe showing improvements in various intermediate outcomes, including hypertension and left ventricular hypertrophy, which appears to be better controlled with daily hemodialysis.

III. Describe a Step-by-Step approach/method to this problem.

Complications in dialysis patients: cardiovascular disease

Cardiovascular disease is the leading cause of death in both CKD and dialysis patients, and accounts for almost 50% of the deaths of patients undergoing dialysis. This is 10-20 times higher in dialysis patients compared with the general population. Traditional risk factors in these patients include older age, hypertension, and hyperlipidemia, along with diabetes in many as well. Hyperhomocysteinemia, malnutrition, and dialysis increased oxidant stress may contribute to cardiovascular risk, along with other non-traditional risk factors such as altered calcium phosphorus metabolism, which can lead to increased vascular calcifications. Cardiomyopathy and left ventricular hypertrophy may also commonly occur. Aggressive cardiovascular risk factor modification should be undertaken for all dialysis patients, given that CKD is considered a cardiovascular disease equivalent, however not much in the way of guidelines exist for management of this particular population.

Whether anemia is associated with an increased risk of cardiovascular events is unclear and debatable. Observational data indicate that low hemoglobin (Hb) < 9 g/dL was associated with high cardiovascular risk and mortality in dialysis patients. By contrary, recent data indicates that also those with a Hb greater than 12g/dL were more likely to suffer strokes. Data from randomized controlled studies had concluded that elevated Hb levels particularly with excessive use of erythropoietin stimulating agents were associated with high incidence of death, MI, and hospitalization for CHF. Current international guidelines indicate dialysis patients should maintain Hb values between 10-11g/dL, and not lower than 9g/dL or higher than 12g/dL.

Mineral metabolism derangements have been shown to have a negative effect on the vascular calcification process, and hyperphosphatemia has been shown to be associated with cardiovascular mortality. Parathyroid hormone (PTH) levels more than 7-9 times the upper normal value and elevated level of fibroblast growth factor-23 (another phosphatonin) are also associated with increased all-cause mortality. Limiting data from prospective randomized control trials have documented that non-calcium based phosphate binders reduce vascular calcifications without however a clear reduction in cardiovascular mortality. Current guidelines to minimize risks are to maintain serum phosphorus at less than 5.5mg/dL and PTH at less than 600 with a normal calcium level.

In dialysis patients with unstable angina or MI, most of the acute management is similar to patients without ESRD. These patients should receive aspirin, beta blockers, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), and/or nitroglycerin.

Optimal use of fibrinolytic agents, heparin, and platelet glycoprotein IIb/IIIa inhibitors is less clear because of the increased risk of bleeding in dialysis patients. Platelet glycoprotein IIb/IIIa inhibitors should be administered; there are no contraindications after the increased bleeding risk has been taken into account. Abiciximab may be the preferred agent in patients with impaired kidney function since it does not require any dose adjustment.

Coronary revascularization can be performed either with coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) plus stenting. CABG is preferred over angioplasty, as rates of restenosis in this population are 70-80% at six months. In general, evidence suggests that the long-term risk of cardiac events and/or death in dialysis patients is generally higher following PCI plus stenting than after CABG, and thus CABG is the preferred method of revascularization.

If PCI and stenting are utilized, the use of drug-eluting stents (DES) are tolerated better than bare metal stenting, with lower rates of restenosis or need for revascularization. Appropriate anti-platelet agents, as needed after placement of DES in the general population, are to be continued, though this is a known risk factor for increased bleeding incidence.

Heart failure (HF) independently predicts early mortality in end stage renal disease. Dialysis patients can be particularly prone to heart failure for a number of reasons, including hypertension, the possibility of underlying amyloidosis or ischemic heart disease, anemia, and high output failure from shunting across chronic vascular access.

On starting dialysis, patients should be evaluated for systolic and/or diastolic dysfunction. All patients should undergo baseline echocardiography and electrocardiography. Echocardiography should be performed after dry weight is attained. Left ventricular hypertrophy (LVH) is a common finding in these patients, and is usually diagnosed by echocardiography. Regression of LVH can be achieved by control of hypertension, correction of anemia with erythropoietic stimulating agents, and possibly correction of abnormalities of calcium phosphate balance.

Evaluation for the presence of coronary artery disease (CAD) is warranted for patients with worsening systolic function, including ejecting fraction (EF) less than 40%, and/or symptoms suggestive of CAD. As brain natriuretic peptide (BNP) levels can be affected by kidney failure, its use for the diagnosis or management of heart failure in patients with ESRD is complex and different values have been reported in the literature for the diagnosis of HF.

Beta blockers (BB), specifically carvedilol, have been shown to reduce risk of death in dilated cardiomyopathy in dialysis patients. Beta blockers, along with ACEI, should be started at low doses and one by one, to avoid hypotension. Aldosterone antagonists are not currently recommended for routine use in dialysis patients with heart failure, given their safety and efficacy effects are not known when used concurrently with BB and ACEI.

Sudden cardiac death (SCD), usually secondary to ventricular arrhythmias, is a significant source of morbidity and mortality in dialysis patient, and accounts for 25% of all-cause mortality. While obstructive coronary disease can be an important contributor, it is likely not the only one. Left ventricular hypertrophy, rapid electrolyte shifts particularly of potassium, derangements in autonomic function and abnormalities in myocardial ultrastructure and function, including endothelial dysfunction, interstitial fibrosis, and diminished ischemia tolerance, may all contribute to increased vulnerability. There is scant data on prevention of SCD, but some therapeutic interventions may be of benefit.

Avoid low potassium dialysate, as dialysis patients who suffered from SCD were more likely to have a potassium level less than 3.5mEq/L or greater than 6mEq/L. Potassium in the range 4-5.6mEq/L is considered the best for survival

Long, daily dialysis, without the volume and electrolyte shifts that occur with conventional thrice weekly dialysis, may also reduce the risk of SCD.

Beta blockers also have conclusively demonstrated reduced risk from SCDs in patients post-MI and CHF. These results may be extrapolated to the dialysis population with dilated cardiomyopathy, as noted above. Patients who received carvedilol demonstrated a 68% reduction in cardiovascular mortality and SCD.

Despite the data from randomized controlled trials supporting the use of implantable cardioverter defibrillators (ICDs) for primary prevention of SCD in high-risk individuals with cardiomyopathy, there are no prospective-controlled data on dialysis patients. Current guidelines state that dialysis patients with an EF of less than 35% who meet other implant criteria could be candidates for an ICD, but survival from noncardiac disease must be expected to exceed one year.

Complications in dialysis patients: infection

Infections associated with dialysis remains one of the most common causes of morbidity and mortality, as well as hospitalization, for patients receiving dialysis. The cumulative annual incidence of infection related hospitalization was 31% for adults, and the annual mortality rate secondary to sepsis was 100-300 fold higher for patients on dialysis treatment compared to the general population.

Access-related infections remain the most common cause of infection in dialysis patients. Types of access resulting in infection include, in decreasing order of incidence, nontunneled central venous catheters (CVCs), tunneled CVCs, AV grafts from synthetic materials, and AV fistulas from the patient’s own blood vessels.

Staphylococcusaureus is the most common microorganism implicated in severe vascular access related bloodstream infections, followed by coagulase negative staphylococci.S. aureus infection has been associated with high mortality, morbidity, and use of heath care resources; the average length of hospital stay for a patient on HD with anS. aureus bloodstream infection is over 50 days. Further, a high incidence of secondary complications, including infective endocarditis, osteomyelitis, septic arthritis, epidural abscess, and infection of intravascular devices have been associated withS. aureus bloodstream infections.

Given the likelihood of repeated hospitalizations, requirement for vascular access, and frequent use of that site in HD patients, these patients are particularly vulnerable to development of methicillin resistantS. aureus (MRSA) infections. The incidence of MRSA in HD patients is 100 fold higher than in the general population. Non-staphylococcal infections are primarily secondary to enterococci and gram negative rods, with human immunodeficiency virus (HIV) patients most susceptible to polymicrobial pathogens, gram negative rods, and fungal pathogens.

Preventive strategies to reduce CVC related bloodstream infections have been studied. Mupirocin cream seems to be effective in reducing risk of bacteremia. A new approach to prevent bacteremia involves the use of antibiotic lock solutions, such as gentamicin with an anticoagulant, both instilled into the CVC lumen at the end of each dialysis session to prevent biofilm formation. However, the risk of bacterial resistance is a subject of ongoing debate, and is currently not standard of care. The most effective preventive strategy is the placement of a fistula as soon as possible.

In dialysis patients, a high index of suspicion should be maintained for catheter related infection. If infection is suspected, the patient should be cultured, with one blood culture from the access site (one from each catheter port) and one peripherally obtained, if possible. In the event of signs of a local access site infection such as a catheter exit site infection, one culture should be also obtained from the site secretions.

Antibiotics should be started immediately after cultures are obtained, broad spectrum antibiotics covering both gram positive and gram negative flora can be instituted, taking into account the increased prevalence of MRSA. A good combination is vancomycin (or daptomycin if allergic to vancomycin) plus gentamicin or ceftazidime, all of which can be dosed with dialysis every 48-72 hours. Once identification and sensitivities are available, antibiotics can be modified.

Repeat cultures should be done in 48-96 hours. If they remain positive, the catheter should be removed, and metastatic foci of infection should be investigated. For example, echocardiography should be considered in patients with prolongedS. aureus bacteremia.

If the catheter is a non-tunnelled line, it should be removed immediately on confirmation of bacteremia, and a new temporary access placed until the bacteremia clears and a new line for dialysis can be placed (preferably a tunneled line). If the catheter is a tunneled line, the catheter should be removed if the patient is:

if cultures are growing a multidrug resistant organism or fungal organism

if there is evidence of a severe site infection such as a tunnel infection manifesting as cellulitis of the site with pus at the access exit site.

A temporary catheter for short-term dialysis access should be placed, and once blood cultures are clear, a new tunneled line can be put in.

For other infections of a tunneled catheter, if none of the above concerns exist, the tunneled catheter may initially remain in place, with a new catheter placed via guidewire 48-72 hours after beginning appropriate antibiotics. Antiobiotic lock therapy may be instilled into the catheter along with systemic antibiotic therapy. Repeat cultures should be checked in these instances to ensure clearance of bacteremia.

Duration of treatment for an uncomplicated catheter related infection should be 4 weeks, and with complications, including metastatic infections, antibiotic duration should be 6 weeks, and evidence of osteomyelitis should be treated for 6-8 weeks.

Peritonitis is the most common serious complication of PD. Patients present with abdominal pain, fever, and cloudy peritoneal dialysate with more than 100 white cells, and the differential with more than 50% polymorphonuclear (PMNs) in the drained peritoneal fluid. Gram stain detects organisms in only 10-40% cases, but it could lead to the early detection of gram negative or fungal peritonitis. Recent improvements in dialysis tubing have reduced the incidence of peritonitis. Most common organisms causing peritonitis are gram positive cocci, followed by gram negative rods.

Most episodes of peritonitis do not seriously affect the efficiency of the peritoneal membrane, have a quick response, and dialysis can be continued without exchange of the catheter. Marked clinical improvement should be observed within 48-72 hours of initiating therapy. If a cloudy effluent with elevated white cells remains after 5 days of appropriate antibiotic therapy, refractory peritonitis is present and the catheter should be removed.

In the majority of patients with PD-associated peritonitis, the infection is localized to the peritoneum and a few cell layers lining the peritoneal cavity. In fact, bacteremia almost never occurs. Therefore, in patients undergoing PD, there is evidence that intraperitoneal dosing of antibiotics is preferable to intravenous dosing, given the increased local concentration with intraperitoneal administration. Most antibiotics can be mixed with the peritoneal dialysate, and dosing for antibiotics such as vancomycin and aminoglycosides can be done based on levels. Treatment length and decisions regarding catheter replacement can be made after speciation.

Empiric antibiotic regimens containing vancomycin and either a third generation cephalosporin or an aminoglycoside are often used until culture results are available and coverage can be narrowed. Guidelines also state that carbapenems or aztreonam can be used for gram negative coverage.

If coagulase negative staphylococci is identified, treatment is usually with vancomycin, and lasts for 2 weeks. Catheter removal is not required.

For streptococci and enterococci, guidelines state the first line therapy is intraperitoneal ampicillin, or if resistant/allergic, vancomycin. Aminoglycosides can be used for synergy. In cases of vancomycin resistant enterococci (VRE), ampicillin can be used if sensitive, otherwise, options include linezolid and daptomycin, and treatment should be between 2-3 weeks.

ForS. aureus infections, catheter removal is usually required, if it is not responsive after 5 days of appropriate antibiotic therapy or early signs of severe infection arise during the initial treatment. Duration of treatment is for 3 weeks, and treatment is with vancomycin. There is some data for decreased relapses post-therapy if rifampin is used for synergy for one week (but cannot be used as a single agent).

Pseudomonal infections must be treated with two antibiotics with differing methods of activity, and catheter removal is required. Duration is 3 weeks of therapy.

Other single gram negative organisms can be treated 2-3 weeks, with a third generation cephalosporin.

Polymicrobial infections suggest an intra-abdominal process, and other etiologies, such as ischemic bowel, perforation, or diverticulitis should be considered. Metronidazole with ampicillin and ceftazidime can be used empirically.

With culture negative peritonitis, a repeat cell count and differential and culture should be obtained after day three with no growth. If the repeat cell count points toward an unresolved infection, special culture techniques should be used to isolate unusual causes of peritonitis, such as fungi, mycobacteria, and mycoplasma. If there is clinical improvement with empiric therapy, the initial therapy is continued and completed for two weeks. If there is inadequate improvement at 5 days, catheter removal should be considered, particularly if early signs of severe sepsis arise.

Fungal peritonitis presents a special problem, patients on PD have a marked incidence of fungal infections when compared to the general population. The cell count is typically greater than 200cells/uL, and the diagnosis is made via culture. If the dialysate is turbid, peritoneal lavage should be done until it clears. Systemic antifungals should be given until speciation; fluconazole can be used empirically unless the patient has had significant exposure to -azoles recently, in which case amphotericin or capsofungin are better choices. Also, peritonitis secondary to fungi always requires catheter removal.

Mycobacterial infection, while not common, should be suspected if no improvement clinically despite antibiotics or episodes of relapsing peritonitis. Treatment is with the typical regimen of rifampin, isonicotinylhydrazine (INH), pyrazinamide, and ofloxacin, with pyrazinamide and ofloxacin continuing for three months and rifampin along with INH given for 12-18 months. Catheter removal is required in these instances.

In most instances of peritonitis, simultaneous catheter removal and a new catheter replacement is usually successful, but is not possible for refractory peritonitis and fungal peritonitis. In this setting, a minimum period of 2-3 weeks is recommended between the time of catheter removal and placement of a new catheter.

Non-infectious access issues

While infection is the most frequent complication of peritoneal dialysis catheters, there are also many significant non-infectious complications. These include inflow and outflow failure, catheter leak, abdominal herniation, external cuff extrusion, and intestinal perforation.

Inflow is much less common than outflow failure, which is incomplete recovery of dialysate instilled intraperitoneally. Inflow and outflow failure occur secondary to constipation, malpositioning of the catheter, migration of the catheter outside the pelvis pouch, intraluminal catheter occlusion (often by thrombus), extraluminal catheter occlusion (adhesions or omentum wrap), or catheter kinking. Symptoms of flow failure include irregular outflow (and/or inflow), fibrin in the outflow, and pain during the outflow (or inflow) of the dialysate.

Outflow failure due to catheter malpositioning usually occurs within the first month of catheter use. Diagnosis is usually made with abdominal x-rays, and treatment involves surgical repositioning of the catheter, though there are times a catheter can be managed and repositioned fluoroscopically. If initial management attempts fail, replacement of a new catheter is required. Surgical open or laparoscopic exploration may be helpful for omentectomy or lysis of adhesions when repositioning or replacing the catheter.

Treating other causes of flow failure involves correction of the underlying cause. Constipation can be treated with laxatives. Thrombus can be treated with heparin, though this should be added prophylactically to each exchange. Alteplase can also be used in clotted PD catheters. Kinked and migration of the catheters typically require similar treatment as malpositioning of the catheter.

Pericatheter leakage involves leakage of dialysate outside the peritoneum into the tunnel or throughout the exit site. It usually occurs soon after catheter placement, and is associated with high dialysate volumes and in those with weak abdominal walls (multiple surgeries, pregnancies) or incomplete healing of the catheter entry into the peritoneum. Those undergoing continuous ambulatory peritoneal dialysis regimen are most susceptible, secondary to the fact that dwells and exchanges occur in association with maximal abdominal pressure, particularly during the awake time of the day and the upright position.

Clinical signs can include subcutaneous swelling around the catheter and diminished outflow volumes, which may be present prior to frank leakage from the exit site. Diagnosis is confirmed by the visualization of fluid around the catheter, which is very high in glucose. Abdominal and genital wall edema may also indicate leak.

Abdominal herniation can occur externally into the abdominal wall or internally into the chest throughout the diaphragm or into the pelvic floor. Prevention of abdominal herniation is accomplished by repair of any abdominal wall weakness or hernia before initiation of PD. External abdominal hernias manifest as protrusions in the wall or genital areas with or without pain, particularly during the dwell time. Internal abdominal hernias are usually not visible during a physical examination and can manifest as intestinal obstruction or dyspnea. Diminished outflow volume is also a manifestation of an abdominal hernia.

To find the area of pericatheter leak and/or an abdominal herniation, a computed tomography (CT) scan with infusion of dialysate containing contrast material is the test of choice. Successful management can be accomplished by decreasing dialysate volume, decreasing exertional activity during the dwell time, or converting the patient to a night time intermittent peritoneal modality in the supine position with the use of a cycler. Surgical repair may be ultimately required for a persistent pericatheter leak and/or an intra-abdominal hernia.

Extrusion of the external cuff implanted in the subcutaneous space is usually associated to a tunnel infection and/or a pericatheter leak. The PD catheter is surgically fixed in place by two velcro cuffs: the internal cuff fixed into the rectum muscle sheet; and the external cuff fixed into the subcutaneous space. The external cuff extrusion is visible during the physical examination and can be managed by treating the associated complication and carefully shaving the cuff. The PD catheter rarely is extruded from the peritoneal cavity due to its fixation by the internal cuff. Surgical replacement of the catheter may be ultimately required.

Intestinal perforation can occur at the time of catheter implantation secondary to direct injury, or months after placement, secondary to bowel wall erosion. This is an uncommon but life-threatening complication. Clues to the presence of perforation include feculent or bloody dialysate, dialysate retention, diarrhea after dialysate instillation, or gram negative or polymicrobial peritonitis. Treatment consists of cessation of PD, catheter removal, IV antibiotics, and surgical bowel repair.

For AV fistula and graft complications, underlying stenosis of the vascular access circuit is an important predictor for graft or fistula thrombosis. Therefore, angioplasty of a stenotic lesion is the treatment of choice to prevent this, along with avoidance of vascular access failure. Symptoms of stenosis include ipsilateral arm edema, difficult cannulation of the access for dialysis, and development of tortuous veins/collaterals in the chest, neck, shoulder, and upper arm, with decreased access flow. Angiography is the test of choice for diagnosis, and greater than 50% stenosis indicates a significant stenotic lesion. More than 90% of thrombosed grafts have a stenotic lesion. Most grafts and fistulas requiring angioplasty have one or more stenotic site.

Angioplasty is recommended for initial management of stenotic lesions affecting dialysis access, and the strategy of pre-emptive angioplasty decreases the requirement for catheter replacement, decreasing risk of infection, etc.

Surgery is ultimately the treatment for stenotic lesions that are frequently recurring or not amenable (or resistant to) angioplasty, as new lesions can emerge over time and potential venous access sites are lost.

Once thromboses have formed, grafts can be treated by mechanical thrombectomy plus angioplasty of the underlying stenotic lesion. Patency after thrombectomy is slightly better for grafts than fistulas. Attempts to treat thrombosis with thrombolytic agents, such as urokinase and streptokinase, has shown promising results, though is not currently offered at all centers.

Tunneled catheters for vascular access in HD is associated with a high number of complications; the most common being catheter dysfunction or poor flow.

Early dysfunction is usually secondary to catheter positioning or technical problems with placement. Fluoroscopy is critical to ascertaining proper position of catheter and reorienting, if needed.

Late catheter dysfunction is usually the result of partial or total thrombosis or a fibrin sheet or central vein stenosis, which can often result in catheter loss.

Extrinsic thrombi can be located within the central veins, and are capable of causing catheter flow problems during dialysis. Angiography is the most sensitive and specific technique for diagnosis. However, ultrasound doppler is much cheaper, and can be used for confirmation if a high clinical suspicion is already present.

When symptomatic thrombus is present the catheter should be removed. Anticoagulation has been the mainstay of therapy. Patients currently are anticoagulated for 3 months after catheter removal, to prevent extension of thrombus.

If, secondary to lack of vascular access sites, the catheter may need to be preserved, the patient should be monitored closely and anticoagulation initiated. Given that the presence of catheter can promote infection, and infected catheter plus thrombus can precipitate septic emboli, these patients are at high risk for infectious complications.

There is currently no proof as to the usefulness of thrombolytics in these situations.

Intrinsic thrombi occur within the catheter lumen or tip, can totally occlude the catheter and present difficulty with dialysis access. Primary treatment of these thrombi include forceful saline flush, or if unsuccessful, infusion of lytic enzymes, such as tissue plasminogen activator (tPA).

If the above interventions do not succeed in resolving the access issue, catheter exchange can be done over a guidewire.

Surgical considerations in the dialysis patient

As with many other issues surrounding dialysis, a paucity of information exists regarding the optimal medication management of patients on dialysis undergoing surgery. Dialysis patients do have increased morbidity and mortality associated with surgery as compared with the general population; which may be secondary to their higher incidences of cardiovascular disease (CVD), difficulties adjusting fluids and electrolytes in the perioperative period, with hyperkalemia being the most common complication, failure to metabolize anesthetics and analgesics properly, increased bleeding complications, and difficult to control blood pressure.

Prior to surgery, dialysis patients should have a set of electrolyte values, a complete blood count (CBC) and coagulation profile. There is no indication for bleeding time to be measured before surgery and its role before a renal biopsy is controvertial. If time permits, hemoglobin can be optimized with erythropoeitin and iron, as blood loss is a common complication of surgery and the postoperative state is characterized by erythropoietin resistance.

The ability to heal after surgery should be maximized by ensuring good nutrition prior to the procedure. Nutritional status appears to be related to appropriate amounts of dialysis; nutritional parameters such as protein catabolic rate and albumin should be optimized prior to surgery. Current minimum recommendations for dialysis dose and nutritional parameters include a Kt/V between 1.3-1.4 in HD, and 1.7 in PD, and 1-1.2 for a protein catabolic rate. Drugs which can impair appetite should also be evaluated, along with therapy to ameliorate gastroparesis, and nutritional supplementation, as needed.

Whether intensive dialysis pre-surgery improves outcomes is not known. Some studies have shown improved outcomes with daily dialysis for a few days prior to cardiac surgery and achievement of dry weight prior to surgery. In general, dialysis should be provided the day before surgery. If dialysis is done immediately prior to surgery, no heparin should be used, and care should be taken to avoid hypercalcemia and hypokalemia, which are common in the post-dialysis period. An estimate of the amount of fluid to be given or lost during surgery should also be taken into account, and ultrafiltration adjusted accordingly.

For urgent surgery, perioperative dialysis may not be able to be done. In this situation, hyperkalemia is the most important abnormality to be addressed. If potassium (K) is elevated, an electrocardiogram (EKG) should be checked; dialysis patients often have an increased tolerance for hyperkalemia, and EKG changes are frequently not seen until K is greater than 6-6.5mEq/L. If no EKG changes are present and the patient has a surgical emergency, the patient should be able to undergo surgery. If EKG findings are present, and dialysis cannot be performed, medical management should be initiated, including calcium gluconate, insulin, and kayexalate. In some institutions, continuous hemodiafiltration can be performed intraoperatively during prolonged surgical emergencies in ESRD patients with hypervolemia, electrolyte, and acid-base disturbances.

Hypertension is common in dialysis patients. Pre-surgery dialysis should aim to optimize volume status via fluid removal with dialysis. However, antihypertensive therapy should be utilized if the pressure remains high despite achieving dry weight. Parenteral antihypertensives can be useful, including IV nicardipine, labetalol, nitroglycerine, fenoldapam or hydralazine (given with a beta blocker to minimize effect of reflex sympathetic activation). If the patient is in the intensive care unit (ICU), IV nitroprusside may also be used with close monitoring of the thiocyanate level.

Cardiac risk status should be carefully appraised, via the American College of Cardiology’s (ACC) guidelines, evaluating the surgical risk, patient’s risk, and functional capacity. When stress testing is indicated, thallium 201 imaging or dobutamine stress echo may be of more use in this population.

An increased tendency to bleed may be present in renal failure. Uremic bleeding correlates most closely with prolongation of the bleeding time, due primarily to impaired platelet function. There are currently no recommendations to obtain bleeding times in dialysis patients routinely as part of the preoperative workup. However, post-operatively, if patient is bleeding, without other causes and with a normal international normalized ratio (INR), partial thromboplastin time (PTT), and platelets, options include measuing bleeding time. Correction of platelet function is recommended with an elevated bleeding time and active bleeding. This can be done by raising the hematocrit (Hct) to 25-30 via transfusion, administration of desmopressin, or cryprecipitate. Dialysis itself can also help.

Perioperative antibiotics should be administered as per general surgical protocols, with dosing adjustments for dialysis patients. Preoperative antibiotics are not routinely recommended for placement of PD or HD catheters.

Pain relief may be provided by a variety of agents, but fentanyl appears to be the narcotic of choice. It is well tolerated, lacks active metabolites, and has an unchanged free fraction. Meperidine and morphine should be avoided, as they have extremely long half lives in dialysis patients.

IV. Common Pitfalls.

Admitting a dialysis patient to hospital, even for non-dialysis related issues, requires a great deal of oversight, continuation of their complex medical therapies, and close monitoring by the physician of electrolytes, cardiovascular and pulmonary status, along with close surveillance for infection.

Diet

On admission, dialysis patients should be started on a renal diet, which is a set of guidelines to minimize buildup of excess volume and certain electrolytes. Sodium is limited to less than 2g/day, and total volume to match their insensible losses and existing residual urine volume, or when anuric, less than 6 cups/day fixed. The diet is also low in potassium and phosphous fixed. A high intake of protein is recommended, as ESRD is associated with significant protein catabolism and many on dialysis suffer from malnutrition.

Malnutrition occurs in 20-70% of dialysis patients, with an increasing length of time on dialysis corresponding with a decline in nutritional parameters. The most readily treatable cause of malnutrition in dialysis is related to underdialysis, which can lead to anorexia and decreased taste acuity. Patients with a low normal Kt/V and low BUN may appear to be well dialyzed, but many of these patients are underdialyzed with poor protein being responsible for the low BUN. This has led to the appreciation that protein intake must be considered when evaluating the adequacy of dialysis. The estimation of the normalized protein nitrogen appearance (nPNA) as an index of protein intake is a part of the dialysis regimen, also known as the normalized protein catabolic rate. The relationship between dose of dialysis and protein intake has been demonstrated in a study, where, as the intensity of dialysis was increased, so did the elevation of the nPNA.

Even in the well-dialyzed patient, there are a number of factors that can impair nutrition:

acute or chronic systemic illness, leading to an inflammatory response.

nutrients are lost in dialysate; protein loss can be up to 20 grams per dialysis, particularly with the use of a dialyzer with excessively high flux or with PD during episodes of peritonitis

gastroparesis or dialysate in the abdomen with PD may impart a feeling of fullness and decrease per os (PO) intake

phosphate binders can also impair taste.

Preventing malnutrition includes a careful assessment of nutritional status in ESRD and starting dialysis before significant malnutrition is present.

A diet providing 1-1.2g/kg/protein is recommended for hemodialysis patients. PD is associated with higher levels of protein loss; protein intake in these patients should be at least 1.2g/kg/day. If nutrient intake cannot be improved by diet alone, oral supplements should be added, escalating up to enteral nutrition and then parenteral nutrition either intradialytic or total, if no other method has good effect. If phosphate binders impair food taste, they can be changed by, for example, switching a calcium for a non-calcium based binder or vice versa.

Gastroparesis may also be a contributing factor, especially if diabetes is the underlying cause of renal failure, and gastric emptying should be assessed if suspected. Medications that improve gastric motility can be given, adjusting their dose to ESRD. Severe gastroparesis may preclude use of oral supplementation or medical treatment; in this case, intradialytic parenteral nutrition may be beneficial.

Correcting acidosis may also help treat malnutrition, given uremic acidosis can increase skeletal muscle breakdown and diminish albumin synthesis.

Electrolytes

There are no specific guidelines of how frequently electrolytes should be monitored in hospitalized patients with ESRD. In ESRD patients adequately supported with dialysis, on an appropriate diet, and free of acute events predisposing to sudden electrolyte disturbances, the blood level of electrolytes are monitored monthly when normal or weekly if abnormal in outpatient dialysis centers. Similarly, blood electrolyte levels can be checked upon admission and then weekly in stable hospitalized ESRD patients. However, electrolytes should be monitored closely in hospitalized patients with ESRD and with increased risks for sudden electrolyte disturbance.

As per the National Kidney Foundation’s Kidney Disease Outcome Quality Initiative (KDOQI) guidelines, serum levels of phosphate should be maintained between 3.5-5.5mg/dL and serum levels of corrected total calcium should be maintained between 8.4-9.5mg/dL, or a Ca*Phos product of less than 55mg/dL. Monitoring of phosphorus is important as hyperphosphatemia has been associated with increased long-term mortality in ESRD, and phosphate is the main factor leading to calcification of the extracellular matrix.

First line to treat hyperphosphatemia can be restricting dietary phosphate to approximately 800-1000mg/day, but in the hospital setting, phosphate binders are most helpful. Non-calcium containing phosphate binders include sevelamer and lanthanum carbonate, while calcium binders include calcium acetate and calcium carbonate. Chosing calcium containing binders over non-calcium containing binders involves evaluating the patient’s serum calcium and whether there is presence of vascular calcifications; calcium containing phosphate binders are associated with increased calcium levels and increased risk for vascular calcifications compared with non-calcium containing binders. Both types of phosphate binder on adequate dose are equally effective controlling hyperphosphatemia.

Associated with hyperphosphatemia in dialysis patients, these patients are prone to hypocalcemia, decreased vitamin D levels, and secondary hyperparathyroidism. If this is not corrected, renal bone disease, referred to as renal osteodystrophy, will develop. This can result in weakness, fractures, bone and muscle pain, and avascular necrosis, and often the disease does not become symptomatic until the patient is undergoing dialysis. To achieve control of secondary hyperparathyroidism, KDOQI guidelines suggest target plasma levels of intact PTH should be between 150-300pg/mL for patients on dialysis. However, the new Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest target plasma levels of intact PTH can be as high as 7-9 folds the upper limit of normal or about 600pg/mL.

Checking intact PTH in hospitalized patients with ESRD patients is not necessary unless patients remain hospitalized longer than a month or undergo parathyroidectomy for tertiary hyperparathyroidism. Intact PTH level decreases suddenly after parathyroidectomy which is used to assess the efficacy of the surgical intervention; otherwise, it takes several weeks to see change in intact PTH level with medical interventions for secondary hyperparathyroidism.

The prevalence of nutritional vitamin D deficiency, defined as less than 30ng/mL, is high in this population as well. To treat the underlying disorder, in dialysis patients with increased PTH levels, calcitriol or vitamin D analogues are first line to lower PTH levels. If that is unsuccessful, calcimimetics, such as sensipar, are recommended. Calcitriol or vitamin D analogues and sensipar must be continued in hospitalized ESRD patients at their pre-hospitalization dose regimen. Vitamin D and analogues should be used cautiously in dialysis patients with high levels of phosphorus (greater than 5.5) and calcium (greater than 9.5), as they can also increase phosphorus levels and promote vascular calcifications.Sensipar should also be used cautiously or placed on hold in patients with hypocalcemia.

Treatment failures are dialysis patients who go on to develop tertiary hyperparathyroidism, which is elevated PTH and spontaneous hypercalcemia, or patients with persistent and progressive elevations in PTH that cannot be lowered despite treatment with vitamin D and cinacalcet. At this time, surgery (parathyroidectomy) can be considered. In patients admitted for parathyroidectomy, the calcium level can decrease suddenly after this procedure requiring a high dose of calcium replacement with active vitamin D and its close monitoring is required.

Hyperkalemia is also a common electrolyte abnormality found in dialysis patients, often in between dialysis sessions. Most dialysis patients with hyperkalemia do not exhibit symptoms, such as flaccid paralysis or muscle weakness, as many of them have been developing the hyperkalemia slowly. Patients who gradually develop hyperkalemia will not show symptoms or EKG changes until the potassium is significantly above their baseline. In general, a patient undergoing dialysis regularly and on a low potassium diet, with K less than 5.5mg/dL and no EKG changes, does not need to be treated.

For hyperkalemia with EKG changes, IV calcium gluconate (1 amp), 10 units IV regular insulin along with dextrose (1 amp), and beta agonists will all work quickly and redistribute the K, causing increased intracellular uptake and decreased destabilization of cardiac membranes, decreasing the risk for arrhythmias. If the patient’s Ca* Phos product is greater than 60, there is an increased tendency to form Ca/Phos complexes leading to calciphylaxis, and calcium gluconate should be used cautiously. Kayexalate orally or per rectum will remove the potassium, but works slower by inducing diarrhea, and can take several hours to a day for full effect. Ultimately, hemodialysis is the treatment of choice to effectively remove potassium in severe hyperkalemia.

In ESRD, there is an almost total impairment of ability to buffer, retain or produce hydrogen ions, leading to metabolic acidosis. Correction of the acidosis is recommended, even in asymptomatic CKD patients not yet on dialysis and with only mild decreases in plasma bicarbonate, or changes in potential hydrogen (pH), as correction of acidosis can slow progression of kidney disease, and decrease uremic skeletal muscle breakdown and inhibition of albumin synthesis, which often leads to malnutrition. Bicarbonate supplementation is indicated to reach a normal serum bicarbonate level of between 23-25mEq/L. Sodium bicarbonate, administered daily is the compound of choice. Sodium citrate may also be used in patients who cannot tolerate bloating associated with bicarbonate therapy, but if the patient is taking any aluminum containing antacids, it should be avoided, as it increases gut absorption of aluminum, which is not dialyzable.

Anemia

Most patients with ESRD are anemic secondary to decreased erythropoietin production. However, prior to initiating therapy with erythropoietic stimulating agents, such as erythropoietin (EPO) or darbopoietin, iron stores must be assessed, and non renal causes of anemia excluded. Diagnosis of absolute iron deficiency in ESRD is defined as a transferrin saturation (TSAT) (iron/total iron binding capacity (TIBC)) less than 20% and a ferritin less than 200.

Absolute iron defficiency in ESRD requires iron supplementation prior to or concomitantly with erythropoietin administration in dialysis patients. Iron supplementation may be given orally in CKD patients not yet on dialysis, but it is preferred to be given IV in dialysis ESRD patients, as oral iron may not have significant erythropoietic benefit. Iron given IV readily and immediately replenish deficient iron stores when started concomitantly with erythropoiesis stimulating agents.

Iron therapy and erythropoietic agents should be utilized for a target hemoglobin (Hb) 10-11g/dL in ESRD patients in dialysis and for a target Hb 9-11g/dL in CKD patients not yet on dialysis. TSAT greater than 20% and ferritin greater than 200 are goal parameters to achieve while all patients are being treated for anemia of CKD. It can be expected that the Hb level would only increase minimally by 0.5-1g/dl/week with appropriate therapy for anemia of CKD; thus, monitoring Hb level daily is not recommended unless acute blood losses are suspected. Monitoring iron studies is recommended once a month and no more frequent than once a week even when iron IV is used to replenish deficient iron stores. There is no role of monitoring erythropoietin level in CKD patients.

Hypertension

Hypertension is a common finding in ESRD. Given that these patients are at increased risk for infarction and stroke, aggressive control of blood pressure (BP) is necessary, though overly aggressive BP control can lead to hypotension at the end of dialysis and limit the amount of volume that can be removed. ACEI or ARB can be used as first line agents, as they can protect any residual renal function, though may increase propensity towards hyperkalemia.

Platelet dysfunction

Dialysis patients bleed much more easily than those without ESRD. Causes for this include abnormal platelet/vessel interaction, caused by altered von Willebrand factor (vWF) and abnormal production of nitric oxide (NO), among other factors. The bleeding tendency in uremic patients can be temporarily corrected by using desmopressin, which causes release of factor VIII:vWF multimers from the endothelium. Dialysis is however the only true way to correct the physiologic abnormalities of uremia, and should be considered urgently in uncontrolled bleeds where other causes have been ruled out. Transfusion is usually not effective in these patients.

Testing

Blood tests commonly ordered in the hospital which are affected by ESRD include d-dimer and lipase, both of which tend to be elevated falsely. Troponin levels are not significantly affected by chronic renal failure or dialysis, and elevated troponins have been shown to be a marker of some sort of cardiac injury, though it is unclear whether it is new or old.